1. Field of the Invention
The present invention provides a method for treating and preventing a subject suffering from peptic ulcer and duodenal ulcer.
2. Description of the Related Art
As generally known a peptic ulcer, also known as PU or peptic ulcer disease, is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. Almost 70-90% of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach. Ulcers can also be caused or worsened by drugs such as aspirin, Plavix (clopidogrel), ibuprofen, and other NSAIDs (non-steroid anti-inflammatory drugs).
Contrary to general belief, more peptic ulcers arise in the duodenum (first part of the small intestine, just after the stomach) rather than in the stomach. Duodenal ulcers are generally benign.
The classification of peptic ulcer by region or location includes:                Stomach (called gastric ulcer)        Duodenum (called duodenal ulcer)        Esophagus (called Esophageal ulcer)        Meckel's Diverticulum (called Meckel's Diverticulum ulcer)        
Furthermore, modified Johnson classifications of peptic ulcer include:                Type I: Ulcer along the body of the stomach, most often along the lesser curve at incisura angularis along the locus minoris resistentiae.        Type II: Ulcer in the body in combination with duodenal ulcers. Associated with acid oversecretion.        Type III: In the pyloric channel within 3 cm of pylorus. Associated with acid oversecretion.        Type IV: Proximal gastroesophageal ulcer.        Type V: Can occur throughout the stomach. Associated with chronic NSAID and ASA use.        
Hyaluronic acid, also known as hyaluronan, hyaluronate or sodium hyaluronate, is generally referred to as HA, which is a natural glycosaminoglycan macromolecule including disaccharides composed of the alternative N-acetyl-D-glucosamine and D-glucuronic acid linked via alternative β-1,3 and β-1,4 glycosidic bonds. HA found in nature with a molecular weight (Mw) between 50,000 Dalton (Da) and a few million Dalton usually has high viscosity.
The species of HA is not only being shown as Mw but also as intrinsic viscosity (η) which is directly related to the Mw of a polymer through the Mark-Houwink-Sakurada (MHS) equation: [η]=KMα. For HA, K is 0.397 and the exponent α is 0.601 dissolving in 0.15 N NaCl at a concentration ranging between 0.01 mg/ml and 0.1 mg/ml (Gomis et al., Arthritis & Rheumatism Vol. 50, No. 1, January 2004, p 316).
The HA can be found in the soft connective tissue in the body of mammals, and the skin, the vitreous humor of the eye, the joint fluid, the umbilical cord and cartilage tissue contains higher volume of the HA. The HA can be applied as the adjuvant agent for the eye operation, or to reduce the pain while movement of the knee and joint of the osteoarthritis patients.
U.S. Pat. No. 5,888,986 discloses a method and related structure for using HA at an effective concentration to treat cystitis, wherein the average Mw of the HA is more than 200,000 Da. There is only one species of HA with a certain Mw been applied in the embodiment thereof. For example, HA with the average molecular weight of 650 KDa or 1,900 KDa is used to treat the cystitis; however, the single species of HA with the certain average molecular weight cannot be used for both prompt treatment and sustained effect.
Richter Gedeon Vegyeszeti Gyar R. T., a Hungarian company, has filed a U.S. Pat. No. 6,656,921 (Pat. '921) on Dec. 2, 2003 in title of Use of zinc hyaluronate against peptic ulcer to disclose that the zinc hyaluronate with Mw between 500 KDa and 1,200 KDa can be applied to treat peptic ulcer.
The preparation of 1.0% Solution of Zinc Hyaluronate of the Pat. '921 is as follows:
Sodium hyaluronate (1.0 g) is swollen in 30 ml of water while constant stirring then after adding 18.75 ml of 0.1 molar zinc chloride solution it is filled to 100 ml with distilled water. The characteristics of sodium hyaluronate used for the preparation of solutions of zinc hyaluronate with various molecular weights and degrees of purity employed in our pharmacological investigations are summarized in the following Table (Pat. '921, page 4, line-31).
Zinc is a heavy metal which may have different effects or side effects on various individuals, or may raise the burden of body health, though it belongs to trace element required by human body. The purpose of Pat. '921 to use zinc is to promote the treatment effect for peptic ulcer. However, the dosage and treatment duration in the clinical must be strictly restricted owing to zinc involved. Furthermore, Pat. '921 only used one species of HA and did not depict or give any embodiment to teach at least two species HA exploited at the same time.
Gomis et al. (Arthritis & Rheumatism Vol. 50, No. 1, January 2004, pp. 314-326) disclosed a comparison among 3 different HAs preparations used as therapeutic agents for osteoarthritis pain in humans in order to establish the degree to which a single application affects the sensitivity of nociceptors in both the normal and the acutely inflamed rat joint. Three HAs were all commercially available. The average Mw of Orthovisc, calculated from intrinsic viscosity and light scattering measurements, is higher than that of Hyalgan (1.3 million versus 0.7 million), whereas Synvisc is about 6 million (Gomis et al., p 316, Table 1). According to the certificate of analysis (COA) of different commercial products, the average Mw has been decided in different polydispersity. The polydispersity revealed in Gomis et al. cannot represent the whole situation in the market.
HA can be defined either by average molecular weight or by intrinsic viscosity which is well known in this technology field (Gomis et al., p 316, Table 1). The specific molecular weight of HA cannot be defined precisely, but could be defined as the content of certain HA is especially high in particular molecular weight (Gomis et al. p 316, FIG. 1). Moreover, molecular weight of HA can be defined by HPLC which is also well known in the art. Some examples are shown as follows:
(a) The molecular weight of hyaluronic acid may be determined according to a conventional manner, for example by gel permeation chromatography (GPC) (U.S. Pat. No. 7,834,173, Page 4, line 49).
(b) High pressure liquid chromatography (HPLC)-GPC analysis reveals that the fraction of HA obtained has a mean molecular weight (Mw) of 5,850, a mean numerical molecular weight (MN) of 3,640 and a polydispersity index of 1.61 (U.S. Pat. No. 8,034,795, example 4, page 22, line 17).
Therefore, the term “average molecular weight” as a definition to distinguish HA is generally acknowledged by skilled artisan in the art.